It has been previously and widely carried out to prepare molded articles containing active ingredients by using cellulose powder as an excipient.
Cellulose powders that were used are known to be microcrystalline celluloses and powdered celluloses, including the following examples.
JP-B-40-26274 describes a cellulose powder having an average polymerization degree of 150 to 375, an apparent specific volume of 1.84 to 8.92 cm3/g, and a particle size of 300 μm or less.
JP-B-56-2047 describes a cellulose powder having an average polymerization degree of 60 to 375 and an apparent specific volume of 1.6 to 3.1 cm3/g and 2 to 80 wt % of a component of 200 meshes or more, and JP-A-06-316535 deals with cellulose powder having an average polymerization degree of 100 to 375, an apparent specific volume of 4.0 to 6.0 cm3/g, and an average particle size of 30 to 120 μm without the substantial presence of a particle of 355 μm or more which is obtained by the acid hydrolysis or alkaline oxidative decomposition of a cellulosic material.
WO02/02643 describes a cellulose powder having an average polymerization degree of 150 to 450, an average particle size of 20 to 250 μm, and an apparent specific volume of 4.0 to 7.0 cm3/g.
JP-A-11-152233 describes those cellulose powders having an average polymerization degree of 100 to 375 which pass through a sieve with a mesh size of 75 μm and of which 70% or more of the total weight remains on a sieve with a mesh size of 38 μm without passing therethrough.
JP-A-50-19917 describes a method for preparing an additive for tablet molding which includes pretreating purified pulp to depolymerize until the pulp has an average polymerization degree of 450 to 650, and then subjecting it to mechanical pulverization treatment such that 50% or more of the resulting particles may pass through a 200-mesh sieve.
JP-A-63-267731 describes a cellulose powder which is pulverized to an average particle size of 30 μm or less. JP-A-63-267731 describes a method of preparation of a cellulose powder having an average particle size of 10 μm or less. This reference describes a powder having a relatively large apparent specific volume.
However, there has been a problem that the cellulose powder obtained by the method disclosed in the above described reference has insufficient compression moldability because the compression moldability of it is low, and thus a tablet with practical hardness can not be obtained. Further, there has also been a problem that when an active ingredient has liquid or semisolid form, exudation of the ingredient and tableting disorder occur at the compression molding of the tablet.
In addition, when a liquid or semisolid active ingredient is formed into a tablet at ordinary temperature, a method that has been previously known, which includes holding the liquid ingredient directly on an adsorption carrier, or dissolving, emulsifying or suspending the active ingredient in water, organic solvent, water-soluble polymer or surfactant before the holding thereof on the adsorption carrier, and then passing a drying process, and further subjecting the resultant dry powder or granule to compression molding, is described in JP-A-56-7713, JP-A-60-25919, JP-A-61-207341, JP-A-11-193229, JP-A-11-35487, JP-A-2000-16934, JP-A-2000-247869, JP-A-2001-181195, JP-A-2001-316248, National Publication of International Patent Application No. 2002-534455, JP-A-2003-161, JP-A-2003-55219. In such a method it has been a problem that there are many necessary drying steps, and thus the costs of equipment which is used therein and the energy used for drying are increased.
Also, JP-A-61-151116 describes a method which involves mixing an active ingredient with a surfactant or a water-soluble polymer in the presence of a nonaqueous solvent, and then removing the solvent, and JP-A-61-225121 describes a method which involves dissolving the ingredient in liquid polyethylene glycol, and then obtaining a powder or a granule, followed by the compression molding. In such a method it has been a problem that the use of the nonaqueous solvent requires the step of desolvation under heating, and thus the costs of equipment which is used therein and energy used for drying are increased. When only polyethylene glycol is used without adding a solvent, no tablet has been substantially obtained. Indeed, only a powder is described in the Examples of these references.
JP-A-57-165392 discloses a method for preparing a tablet containing an active ingredient and 10% or more of fat and oil based on the weight of the active ingredient. However, in such a method the active ingredient, the fat and oil component and an excipient must be formed into a dry granule using a compression roller. The extra step and the extra equipment therefor increase costs.
JP-A-58-194808 describes a chewable tablet consisting of a mixture of a pretreated active ingredient composition composed of a fat and oil absorbing material, which is a typical crystalline cellulose having an edible fat and oil absorbed therein, and a binder, an antioxidant, a flavor and/or a colorant, a pretreated active ingredient composition composed of an active ingredient particle mixture, an edible oil, a binder, an emulsifier, a flavor, and a coloring agent, wherein the active ingredient particles are coated with other components such as the binder, and a pretreated auxiliary composition for direct compression tableting composed of a binder and a flavor. However, in the method described in the reference it has been a problem that in order to obtain the three kinds of compositions, the respective pretreatment steps are required and such additional steps make the preparation method complicated, and thus the cost of equipment which is used therein is expensive. In addition, such a method does not satisfy the purpose of obtaining a tablet having high hardness because it provides only a tablet with low hardness.
JP-A-8-268914 discloses a solid pharmaceutical composition containing an oil or an oily substance, an active ingredient, and a water-insoluble non-bridged polymer excipient which has an average particle size of more than 150 μm and is capable of binding water, and a method for preparing the same. However, in such a method it has been a problem that the oily substance, the active ingredient, water, and the specific water-insoluble non-bridged polymer need to be stirred with high shearing force and the equipment used for this method is necessary.
JP-A-2001-335469 describes a method for producing a solid preparation that is excellent in the elution of a water-insoluble bioactive ingredient and further has a proper hardness. The method includes mixing the bioactive ingredient, a nonionic surfactant and/or an anionic surfactant and allowing a water-swelling polymeric compound with a specific surface area of 5,000 cm2/g or more to support the mixture, to which a general-purpose cellulose powder is then added, followed by the compression molding. In such a method, it has been a problem that the steps of mixing the drug with the surfactant(s) and allowing the specific water-swelling polymeric compound to support the mixture are necessary, and such additional steps make the production method complicated, and thus the cost of equipment which is used therein is expensive.
As described above, conventional methods have not been able to solve the problems that complex preparation processes lead to the increased cost of equipment and energy and that practical tablet hardness is not achieved at compression molding, generating exudation of liquid active ingredient and tableting disorder.
An object of the present invention is to provide a cellulose powder which is excellent in compression moldability and liquid retention when used as an excipient in the preparation of molded articles containing various active ingredients. Particularly in the preparation of a medical tablet, the present invention does not generate exudation of liquid active ingredient and tableting disorder and can produce a tablet having sufficient hardness in a simple and easy production process.